Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity
By M. Milanski, G. Degasperi, A. Coope, J. Morari, R. Denis, Dennys E. Cintra, D. Tsukumo, G. Anhê, M. E. Amaral, H. Takahashi and 6 more. Journal of Neuroscience, 2009
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In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.
Subfields: Behavioral Neuroscience, Endocrine and Autonomic Systems, Epidemiology
View Paper: https://www.semanticscholar.org/paper/a071f649e243020e72dcfd3c2f2cf2ee36f8b792
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Citations in the corpus
- Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease (2014, background): “In animal models of T2D and obesity, an inflammatory response in the hypothalamus, notably via activation of TNF-a and the IkBa kinase (IKK)-b/nuclear factor-kB pathway, is an important part of the mechanism underlying pathogenesis (69,70).”
- Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. (2010, background): “There is evidence that SATs, which were a major component of the HF diet used in this study, can act as ligands at the TLR4 receptor (31, 36).”